Duchenne muscular dystrophy (DMD) and the allelic Becker MD is one of the most common human genetic disorders. DMD/BMD is caused by mutations in the dystrophin gene, and is characterized by progressive muscle wasting. BMD displays a later onset and slower progression, with many patients living well past middle age. Improved respiratory support is also helping many DMD patients live into their fourth decade, and both groups ultimately display a profound loss of muscle mass that is replaced by fibrotic and adipose tissues. Genetic therapies for these and other muscle wasting disorders would be facilitated by methods that allow efficient gene transfer to muscles of adult and old patients, yet virtually all studies of gene transfer to date have focused on young mice. This project explores the ability to deliver therapeutic genes to muscles of aging mice, with a focus on the interplay between muscular dystrophy and aging. Since many muscle wasting disorders typically manifest in older individuals, it is important to focus on age related phenomena that inhibit or otherwise impact the ability to improve the physiological state of the target muscles. The ability to genetically modify muscles of old animals would facilitate the use of similar approaches for other muscle wasting disorders, such as muscle loss during aging (sarcopenia) and muscle atrophy associated with cancer (cachexia). Our primary focus will be on aging normal and mdx mice, a model for DMD/BMD. We will evaluate the ability to target muscles of adult and old mice by systemic delivery of adeno-associated viral (AAV) vectors and will identify and circumvent barriers to gene delivery in elderly animals. We will use these optimized methods to generate new mouse models and methods for studying disorders and phenotypes that are exacerbated by, or associated with, advanced age. Finally, we will develop methods to modify muscle structure and function in elderly animals, with a focus on old WT and dystrophic mice by co-delivery of improved mini-dystrophins and modulators of muscle mass. PUBLIC HEALTH RELEVANCE: This work is highly relevant to developing genetic-based treatments for the muscular dystrophies, which are common inherited disorders that affect young, adult and elderly individuals. These same methods should also be broadly applicable to developing interventions to slow or halt muscle wasting associated with normal aging.